Follicular small cleaved cell lymphoma (FSCCL) is a low-grade lymphoma with indolent course with the characteristic chromosome translocation t(14; 18)(q32;q21) resulting in rearrangement of the bcl-2 proto-oncogene. Bcl-2 is over-expressed, abrogates apoptosis, and results in cell accumulation. Sixty-five percent (65%) of cases progress to large cell lymphoma within 10 years. Bcl-2 rearrangement or over-expression above may not be sufficient for lymphomagenesis, suggesting that other genetic events play a role in the development and progression of FSCCL. Karyotypic analysis of FSCCL is limited to metaphases of dividing cells and may not be representative for the cytogenetic abnormalities and for clonal heterogeneity, as these tumors exhibit a characteristically low growth fraction. Fluorescent in situ hybridization (FISH) allows the cytogenetic analysis of metaphase and of non-dividing interphase cells and is a powerful tool for the analysis of subpopulations of the malignant clone. FISH analysis has already demonstrated the emergence of subpopulations with trisomy and tetrasomy of chromosome 12. We propose to investigate prospectively samples from patients with FSCCL for emerging subpopulations with numerical abnormalities of chromosomes 3, 7, 12, 18, and y and for deletions such as 17p-, 6q-, and 1 p-. These changes will be correlated with progression of disease, relapse, or transformation. Samples also will be labelled with BUdR and the fraction of cells in 5- phase will be determined for each cytogenetically distinct subpopulation. Patients will be treated uniformly with standard therapeutic protocols. In addition, expression of bcl-2, as determined by Dr. T. McDonnell, will be correlated with cytogenetic results. Lymphoma cells from different sites in the same patient (lymph node, bone marrow, blood) will be compared to investigate possible associations between cytogenetic abnormalities and site of involvement. The novel technique of Comparative Genomic Hybridization (CGH) will be applied to the sequential study of FSCCL. DNA from involved lymph nodes will be comparatively hybridized to normal metaphase chromosomes with normal DNA and with DNA from subsequent samples from the same patient. We expect these studies to reveal new genetic abnormalities in FSCCL and to provide insight into the genetic changes underlying disease progression.